CA1312085C - Dihydropiridine compounds having unique pharmacological effects, and the process for producing them - Google Patents

Abstract

NO? DIHYROPIRIDINE COMPOUNDS HAVING
UNIQUE PHARMACOLOGICAL EFFECTS, AND
THE PROCESS FOR PRODUCING THEM

ABSTRACT OF THE DISCLOSURE

Novel dihydropyridine compounds of the general formula (I) and salts thereof and processes for producing same.
(I) wherein R1 and R2, which are the same or different, each represents a C1 to C10 alkyl group, a lower alkyl group which is interrupted by oxygen atom(s), or a lower alkyl group substituted by C3 to C6 alicyclic group(s); R3 and R4, which are the same or different, each represents a lower alkyl group; R5 and R6, which are the same or different, each represents a hydrogen atom, a nitro group, a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a lower alkylsulfonyl group, or a lower alkylsulfinyl group; R7 and R8, which are the same or different, each represents a hydrogen atom, a halogen atom, a cyano group, a lower alkoxy group, or a lower alkanoylamino group, or R7 may combine with R8 to form a naphthyl group together with the adjacent phenyl group;
A represents a single bond, z vinylene group (-CH=CH-), or a ethylene group (-C?C-) B represents a single bond or -CH2O-; and m and n, which are the same or different each represents 0 or an integer of 1 to 5. The compounds of the invention are useful in the management of ischemic heart diseases and hypertension.

Description

8 ~
SPECIFICATION

TITLE OF T~TE INVENTION
NOVEL DI~IYDROPYRIDINE COMPOUNDS ~IAVING UNI~?UE PHARMA-COLOGICAL EFFECTS, AND THE PROCESS FOR PRODUCI~G THEM

BACKGROUND OF Tl~IE INVENTION
It is known that certain dihydropyrldine derivatives have a Ca2+-antagonistlc action, and are highly useful for the treatment of various cardiovascular disorders such as angina pectoris, myocardial infarction, hypertension and cardiac arrythmia. It is further known that beta-adrenoceptor blocking agents are also useful for the treatment of such cardiovascular disorders.
However, the mechanism of actlons of dihydropyridine derivatives is entirely different from that of beta-adrenoceptor blocking agents. That is, beta-adrenoceptor blocking agents reduce heart rate, cardiac output, stroke volume, cardiac work and myorcardial oxygen demand whereas, C~2+-antagonists improve left ventricular function due to their coronary vasodilating and systemic vasodilating effect (reduction in afterload) and also inhibit coronary vasospasm.
Recently it has been reported that a combined adminlstration of a (3~2+-antagonist and a beta-blocker can achieve maximal symptomatic improvement in clinical angina pectoris. [Bassan, M. Weiler-Ravell, D. and Shalev, O.: Additlve antianginal effect of verapamil in patients receiving propranolol; Br. Med. J., 284, 1067 (1982)]. Further ~.

it has been reported tha-t a combined administration of such two kinds of drug can be recommended for the treatment of hypertension, since the side effects of either drug are almost abolished or inhibited by the combination administration of both drugs. That isj beta-blocker inhibi-ts a CA2+-antagonist--induced reflex increase of heart rate; and beta-blocker completely inhibit a CA2+-antagonist-induced increase of plasma renin activity.
[Acki, A., Kondo, S., Mochizuki, A. ~ et al;
Antihypertensive effect of Cardiovascular CA2+-antagonist in hypertensive patients in the absence and presence of beta-adrenergic blockade; Am. Heart J~, 96, 218 (1978)].
Thus, it would be expected that a compound having both Ca2+-antagonistic and beta-blocking activities is of interest in the management of ischemic heart-diseases and hypertension. In particular, it would be expected that beta-blocking activity is heart-selective, that is, cardiac beta1-adrenoceptor blocklng activity for the above clinical fields. Thus the purpose of this invention is to provide novel compounds which have both the actions (namely, Ca2~~-antagonistic activity and adrenergic beta-receptor blocking activity) and the production me-thods for the compounds. Further purpose of this invention is to provide some novel compounds which have Ca2~-antagonistic activity and cardiac beta1~adernoceptro blocking activity.

DETAILED EXPLANATION OF THE IN~ENTION
The compounds of this invention are novel compounds which have unique pharmacological effects.

~ 6669A/sza--d2 -The compounds of this i~vent~on are those of the ge~eral for~ula (I) and salts thereof:

R6 ~ (CX2)m~~~(C~2)~ NHCH2C -B- ~ R7 R OOC ~ RC40R (I) . 1 2 whereln R and R , which are t~e same or difrerent, each represents a Cl to C10 alkvl grou~, a lower aIkyl : group which is inte~ ted by o~ygen atom(s?,. or a : lower alkyl g~ou~ substituted by C3 to C6 alicyclic group(s); R3 and R4, wnic~ are the s~me or dif~erent, each represents a lower alkyl group; R5 and R6, which ~are the same or different, each re?resen~s a hydrogen 1' atom, a nitro group, a haloge~ atom, a lower alkyl grou~3. a lower alkoxy group~ a lower alkylt~io group, a lower alkylsulfonyl group, or a lower alkylsulf~nyl .
group; R7 and R8, which are the same or different, each represents a hydroge atom, a halogen a~om, a cyano or group, a lower alkoxy grou~,/a lower alkanoylanino group, or R7 ma~ combine with R to fo.rm a nanhthvl gr2u~
-. together with the /adjacen~ phenyl grou~;
t-CH=CH-) A represents a sin~le bond, a vinylene group/~ or a (--C_C--) ethynylene g~oup/; B represen~s a sm~Le bond or -CH20-;
and m and n, wnicn are the same or dilferent, each ~ 4 ~ 2 ~ ~

re?resen~s O or an integer of 1 to 5~
The above symbols have the same signiflcances hereinafter.
This in~ention also relates to the process for producing the compoundsof formula (I), and ~he~r salts and pharmaceutical composition containing the co~pounds of formula (I) and/or the~r salts.
UneYamined Ge~man Paten~ Publication ~o. 3~07982.
and Belgian Patent 893984 disclose certain dihydro-pyridine compounds. The former discloses dihydro-pyridi~e comDounds wherei~ the 4-posi~ion phenyl grou~
has a alk~l group, a nitro group, a alkogy group, and/or -Xl-~l-Yl (whe~ein Xl is an ox~gen atom, Bl is a alkylene g;ou~1 and Yl is a phe~yi group substituted by a halogen atom or a alkyl group, etc. or others), or othe s. The latte_ discloses dihydropyridine co ounds wherei~ the 4-phenyl group has a nitro group, a phenyl-2n~or ~
alkylthio group,/ a phenylalkoxy group, erC.
The compounds pf this invention have entirely differe~t chemic~l structures--from those of the above-mentioned prior art ccmpounds , and show unique pharmacological effects since they possess both Ca2+- .¦
antagonistic and adrenergic beta-rece?tor bloc~ing activities.In addition, some of the comDounds o~ this invention have also other advantageous pharmacological ac.ions such as cardiac betal-adrenoceptor blocking activity, int-insic sym~hathomimetic activitv and/or - 5 - ~3~

The te~m "lower~ the foregoing definitions means a straigh~or branched carbon chain having 1 to 5 CarDon atoms. Thus exam~les of the "lower alkyl"
are me~hyl, eehyl, propyl, iso~ropyl, butyl, iso-,, butyl, sec-butyl, ter~-butyl, pentyl (amyl), iso-pen~yl t te~t-pentyl, neopentyl, l-methylbutyl, ~-methylbutyl, 1,2-dimechylpropyl, l-ethylpropyl.
The e.~amples of the "lower alkoxy" are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, ter~-butoxy, pentyloxy (amyloxy), isopentyloxy, tert-pentyloxy, neopentyloxy, 2-methylbutoxy, 1,2-dimethyl-propoxy, l-ethylpropoxy. The examples of "lowes alkyl-thio" are methylthio, ethylthio, propylthio, isopropyl-thio, butylthio, sec-butylthio, tert-bu~ylthio, pentyl-thio, neopentylthio, 2-methylbutylthio 7 1, 2-dimethyl-propylthio, 1 ethylpropylthio. ~xam~les of "lower alkylsulfonyl'l - are methyl-sulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, isobutylsulfonyl, pentyl-e~am~les of sulfonyl; and/"lower alkylsulfinyl" are methylsulfinyl, .ethylsulfinyl, propylsul~inyl, butylsulfinyl, isobutyl-sulfinyl, pentylsulfinyl. F~amples of "lower alkyl ~ to Csubstituted by/a~icycl~c group(s)"are cyclopropyl lower alkyl, cyclobutyl lowe_ a'kyl, cyclopentyl lower aikyl, cyclohexyl lower alkyl, Th~s "C3 to C6 alicyclic group"
eans cycloalkyl of 3 to 6 C at~;etc. T~e lower alkyl may ~1, be substituted,at any position(s) of the lcwer/ by C3 ~o C6 alicyclic group(s).

6 i ~2~

~xamples of l'lower alkanoylamino" are acetylamino, propionylamino,bu~ylamino,is~bu~lamino, vale_ylamino, isovalerylamino, pivaloylamino.
As the examples of "lower alkyl which is interrupted by oxygen atom~5)'there are methox~methyl, l-met~oxyethyl, 2-methoxyethyl, l-methoxypropyl, 2-methoxypropyl, 3-methoxypropyl, l-methoxy-l-methylethyl, 2-methoxy-1-methylethyl, l-methoxybutyl, 2-methoxybutyl, 3-methoxy-butyl, 4-methoxybu~yl, 3-methoxyl-1-methylpropyl, ethoxy-methyl, l-ethoxyethyl, 2-ethoxyethyl, l-ethoxypropyl, 2-ethoxypropyl, 3-ethoxypropyl, propoxymethyl, iso-propoxyme~hyl, l-propoxyethyl, l-isopropoxyethyl, 2-propoxyethyl, 2-isopropoxyethyl~ etc.
As the e~amples o~ "Cl to C10 alkyl" ~n the foregoing efinitions for Rl and R2, there are the above-mentioned in addition lowe_ alkyl, and ~the~ alkyls such as hexyl, isohe~yl, l-methylpentyl, 2-methylpe~tyl, 3-methylpentyl, l,l-di-methylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2 dimethylbutyl, 2,3-d' ethylbutyl, l-e~hylbutyl, 2-ethylbutyl, 1,1,2-tr~methylpropyl, 1,2,2-trimethylpropyl, l-ethyl-l-methylpropyl, l-ethyl-2-methylpropyl, heptyl, l-methylhexyl, 2-methyl-hexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, - l,l-dimethylpentyl, 1,2-di-methylpentyl, 1,3-dimethylpentyl, 1,4-d~methylpentyl, 2,2-dimethylpentyl, 2,3-diemthylpentyl, 2,4-dimethylpentyl, 3,3-dimethylpentyl, 3,4-dimethylpentyl, l-ethylpentyl, 2-ethylpentyl, 3-ethylpentyl, 1,1,2-trimethylbu~, 2~

1,1,3-t~~methylbu~yl, 1,2,2-t_imethlbutyl, 2,2,3-t_imethylbutyl, l-ethyl-l-methyl'ou~yl, l-ethyl-2-methylbutyl, l-ethyl-3-methylbutyl, l-propylbutyl, l-isopropylbutyl, octyl, 6-methylhe?tyl, nonyl, 7-methyloctyl, decyl, 8-methyl~onyl. Thus "Cl to C10 alkyl" are straight or branched carbon chain alkyl having 1 to LO carbon atoms.
As the examDles of "halogen", there are chlorine, bromine, iodine, etc.
Some of /the co3~ounds of formula (I) can form salts thereof, and the salts of the compound (I) Lnclude pharmaceutically acce~able salts or pharmacologically acceptable salts.
E~amples of such salts are salt~ of inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid; and salts of organic acids such as formic acid, acetic acid, oxalic acid, citric acid, succinic acid, fumarlc acid, maleic acid, tartaric acid, me~hanesulfonic acid, ethanesulfonic acid, etc.
~he c~mpounds of this invention include compounds the having_asymmetric carbon atom(s); and inlcase of such co ounds, there are optical isomers. Thus, this invention includes all of the isomers such as racemic compound, optically actlve isomer, diastereoisomer.

g ` ~3~$~

Ihe comDounds of this lnvention can be produced by ~arious processes; ~ypic~l production processes are e~plained hereinaf~e_:
PrQcess 1:

R6 ~ O--( C~ ~m ~ ~--~ CE ) --NX
RIOOC ~h~ COOR2 + C --f~I-- B~ R8 (lr) (m) R7 RS

- ~ ~ 2 ) m A ( C~2 ) ~ HCH2 CH--3~
R OOC ~ COOR ( I ) R 3 ~ R

Compounds (I) can thus be produced by reacting ~ substituted dihydr.opyridine derivative (II) (which have amin~ side chain as the substituent of phenyl at 4-position of the dihydropyridine ring) with an epoxy compound (III).
A~ equimolar or excess molar amount of eithe_ of the com~ounds(II) and (III) is used for the reaction, and t~ reaction is performed in the absence or presence of a solvent which does not take part in the reaction.

~ ~ 3 .~
g alcohol, (e.g. methanol, ethanol, isopropanol, etc~), ethe~ (e.-g. ethyl ether), ~etrahydrofuran, e~hyl acetate, dime~hylform2mide, e~c. The reac~ion can be performed at room temperature or under heating. The reaction time maJ be changed according to other reaction condition such as the solvent, etc.
Process 2: - -r~ .
~ 2)m~~ X
P.;Ooc ~ ~OOP~ + E2.~2C~-.5 ~
R' P.- OE R
~V~ (~) R7 R ~ o(c~ ) -A-(C~ C~ C3-3- ~ R8 2 m ~ n 21 R-ooC ~ ~ COOR2 (I) R3 ~ R4 In the above fo~as, X represents a halogen atom or an organic sulfonic acid rad;~l, and hereinafter has the same significance.
. _ . _, . .
Compounds ~I) can thus be produced by reacting dihydropyridine derivative (IV) (whichhave halogeno-s~stituted /side chain or organic sulfonic acid radical-substituted side chain as the substituent of 4-phenyl of the dihydropyridine ring) with amine derivative (V) .
Practical e~amples of "haloPen" for X are chlorine.

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bromine, iodlne; and "organic sulfonic acid radical"
for ~ are alkanesulfonic acid radic~l (~cnYlcxv) such as oxy methanesulfonic acid radical (methanesulfonyl~, ethane~
sulfonic acid readical (ethanesulfony~ ; and aroma~ic sulfonic aoid radical such as toluenesulfonyl acid radical (toluenes~on~loxv), benzenesulfonic acid radical (benzenesulfonyloxy).
In the case of using dihydropyridine derivative _subs~t~ted having halogeno/ side chain as the substituent of 4-phenyl of the dihydropyridi~e ring, the reaction can be performed in the presence or absence of a solvent.Any solvents which do not take part-in the reaction can be used. Ex~mples of the solvent usually used are organic solvent such as benzene, ~oluene, xylene, dimethylformamide, dichloromethane, dichloro-ethane, methanol, ethanol. It is preferred that the re-c'ion is pe-~o~ed by reac~Ing the c~pound (IV) with n ea.uimol2r or eYcessive molar amount of the compound (V). The-reaction is usually performed at room tem~era~ure or under heating, or under reflux.
Accodring to the kind of reaction, it may be preferred for smooth reaction to operate in the presence of a base. Examples of such a base are organic ' bases such as pyridine, picoline, N,N-dimethylaniline, - trimethylamlne, t~iethyla~ne, N-methylmor^pholine,/dimethylamine (that is, secondary or tertiary amines); and inor~anic bases such as sodium carbonate, potassium hydrogencarbonate. In (dialkylation, etc.) order to avoid side-reactions/which ~av be occur, j, ~ 3 ~
~ 11 -it ma~ be adopted to pro~ecl amino group or the com~ou~d (V) and the~ react the ami~o-protec~ed com~ound Wit~
t;~e c~m~ound (IV), and release the protec~ive grou~ af~er ~ n or~r to pn~de the ~s~d ~ound (I) se~ ~ velv the reaction~ Plac~ical e~am~les of the protec~ive group for an amino grou~ are toluenesulfonyl grou~, a~ acet71 group, a phe~acylsulfo~yl g~ou~, a t-ifluoro-methanesulfo~yl group, a bis-~e~ze~esulfonyl group. The releasing of the pro~e~ti~e groups ca~ be carried out by hydrolysis ~ conventlo~al manner. Ih~s~ hydrolysis may be acid- or alkali-nycrolysis.

In the c_se or us~cg aih~dro~yrid~ e c~ va~_ve SUl f o~ic ha~ a org~nic/ac~d raoIc^l-su~s~irlted sic~ c:~a_n as the suDs.irue~t~or 4-~henyl cr the dihyoro~yrid~ne rin~, &n esu~olar or e~c_ss molcr a~ou~t or the compou~d (~) is prere_ably reac-ed with the c~cDou~d (IV) having or~ic s-~ o~ic add ~-~oic-~- l suDs~t~ted side c3a~n. Ihe _ ¦
reaction-is usually-pe_ or2ed-a~ room te~arature or u~der cooling. rne re3c.ion is usuall~ per_or~ed ir~ ~
a (organ c) solve~t whic~ do ~ot take par~ in ~e - ¦
re3ction,--and e.~am~les or the solvent are ethe_, me~hanol, ethanol, toluene, tet_ahydroruran. rne reatioz time may be changed accordinc to the ki~d or star-ing material and solvent, and the re~c.ion cond-tions suc:~ as the 12 ~ g P ocess 3:
~\ ~
~ ~ O- (CEI2 ) A (CY2 ) n ~ ~) p~l 00C~ C~:)OP.- 1 E. ~C~. C~ R8 p~ 7~ ) P7 ~ 2)mA(C~)n,~C~=N~CE. C~
RZOOC ~ OR- ~) O~ 7 R ~ (C~2 ) m~~~ (C~2 ) -~C~2CE~-3- ~R8 R OOC ~~ COOR2 1H R
R3 ~\R4 ( I ) In the ~x~e formNla, n' represents 0 or an integer of 1 to 4~ and hereinafter has the same signi~icance.

Compounds (I) can be prepared by reacting dihydro-pyridine derivative ~I)~which have formyl-substituted side chain as the substituent of 4-phenyl of the dihydro-pyridine ring) with amine derivative (V) to give a Schiff base (VII), and then reducing ~he Schiff base in the ~ounds under a condition which do not reduce any nit-o grou~.
,to form the SC~iff base of a solvent. It is preferred to perform the reaction in a solvent. Any solvents which do no-t take part in the reaction can be used. ~xamples of the solvent used are organic solvent such as benzene, and alcohol such as methanol, ethanol. The reaction is usually performed by reacting the compound ~II) with an equimolar or excessive molar amounl of the compound (V). The reaction is usually performed at room temperature or under heating, or under reflux. According to the kind of reaction, potassium hydroxide may be added in the reaction system, and/or it may be preferred to remove water formed in the course of the reaction by using Dean-Stark trap.
In the step of reducing the Schiff base, a reducing agent may be added to the reaction solution containing the Schiff base formed (without isolating the Schiff base formed).
As the reducing agent which do not reduce nitro group and can selectively reduce an imino group in the Schiff base to give the aimed compound (I), there are, for example, boron compound such as sodium borohydride, lithium borohydride, sodium borocyanohydride. The reducing reaction is performed in an organic solvent such as alcohol (for example, methanol, ethanol, etc.), acetic acid, etc.; or water. The solvents may be used alone or in appropriate combination. The reaction is usually performed at room temperature or under heating. According to the kind of reaction, it may be preferred for smooth reaction to operate in the presence of a base in order to -r~ J-~. \..

~3~2~

maintain the reaction sys~em at neutral or basic state.
In such case, methylamine~ ethylamine, propylamine, dimethylamine, potassium hydroxyde, sodium aceta~e, etc.
may be added into the reaction system.
P.ocess 4:

R6~ (CE32)m-A~ 2)n ~.lH2 R'OO~ ~ COO~~ 1 X- C~7 C~ - B.-~R78 R' ~ OE ~ o E (~) R-ooc ~ (C~)m-~-(C~ C~ CR-~- ~ R7 ~ (I) R3 ~ \R4 - - - Compounds (I) can be produced by reacting a compound (II) ~th a compound (VIII) (halide compound or sulfony~ compound). The reaction conditions are al.most the same as those of the before-mentioned Process ~ 3 ~

Starting ma~e~ials(II) may be produced by the method desc.ibed in the Reference ExamDlesof this application, r other suitable reaction process. Among star,ing having organic sulfonylOxv mate_ials ~IV), dihydropyridine c~oInds /can be produced by reacting organic ~ c~1 halide with a dihydro-pyridine compound having hydroxyl-substitued side chain at 4-phënyl of the dihydropyridine ring; and dihydro-pyridine co~ou~ds having halogeno-substitued side chain can be produced by the method desc-ibed in the Reference Examplesof this applicatlon.
(VI) Staring ma~erials/can be produced by various methods.
For example, a compound (IV) is reacted with Grignard reagent and orrho formic acid ester, and then the formed comDound is hydrolyæed to give ~e com~ound (VI).
A free form of the formula (I) com~ound or a salt of compound (I) can be obtained after the above be p~duced by reactions. A salt of the formula ~I) compound may performingthe foregoing prod~otion proo~ss using a sal~
of the starting com~ound, or by applying a salt-forming reaction to the free formula (I) com~ound.
The formual (I) com~ou~ds and salts can be separated and purified in ordinary manner, such as extrac.ion with organic solvent, crystallization, column chromatography.
In the compounds o~ this invention, there are various isomers such as racemic compoud, optically active isomer, diastereoisomer, etc. alone or in combination. A single isomer can be obtained using a suitable starting material, or by a usual resolution method. ~ applying Lrac~ional The compounds of this invention of the formula (I) and their salts thereof possess both Ca2 -antagonistic and beta adrenoceptor blocking avtivities.
Furthermore, some compounds of this invention possess cardiac betal-adrenoceptor blocking activity, intrinsic sympathomimetic activi~y (ISA) or alpha-adrenoceptor blocking activity. Thus the compounds are useful for the treatment or prevention Q~ ischemic heart diseases such as angina pectoris, myocardial infarction, and also useful for the treatment or prevention of cardiovascular disorders such as hypertension and cardiac arrythmia without causing side effect.
The compounds of this invention also possess cerebral vasodilating and central nervous system improvlng action in additon to their cardiovascular actions. So the compounds of this invention may be also useful agents for inhibiting cerebral vasospasm and improving central nervous system.
These pharmacological properties of the compounds of this invention were evaluated in the following pharmacological experiments. The compounds of this ---i-nv-ention lowered blood--pressur~ and-increased coronary blood flow after intravenous injection (effective dose range; 0.01 to 3 mg/kg i.v.), dilated coronary artery after intracoronary injection (effective dose range; 1 to 300 ~9 i.a.), produced beta-adrenoceptor blocking effect after intravenous injection (effective dose range; 0.1 to 3 mg/kg i.v.) and also reduced cardiac work and myocardial oxygen consumption.
These pharmacological experiments also showed that the antihypertensive and coronary vasodilating activities of some compounds of this invention lasted longer than those of known dihydropyridine derivatives.
The pharmacological effects of the compounds of this invention are shown in the following test results with the test méthods.

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~ethods (1) Hemod~namic effects ~ ongrel dogs of either sex were anesthetized with pentobarbital sodium (30 mg/kg iv). The animals were artificially ventilated with room air. The chest was opened at the left 4th intercostal space. ~ean arterial blood pressure (~BP), heart rate (HR), left ventricular pressure (LVP), max. dLVP/dt, mean pulmonary arterial blood pressure (~PAP), cardiac output (C0) and coronary blood flow (Cor. BF) were measured. The test compounds were injected into the femoral vein. Hemodynamic effects of these compounds were compared with that or well known Ca2+-dntagonists.
Table 1 (column 1) indicates the percent changes of ~BP and Cor. BF from control values induced by intravenous injection of test compounds.

(2) Coronary vasodilating effects ~ ongrel dogs of either sex were anesthetized and ventilated as previously described. A thoracotomy was performed at the ~th intercostal spac .
Following an intravenous injection of heprin (1000 units/kg), blood from the distal end of the cannulated carotid artery was pumped into circumfle,~ branch o~ the left coronary artery using a servocontrolled peristaltic pump which maintained a constant perfusion pressure oF 120 mmHg by means of a pump controller. An electromagnetic flow probe was inserted in the circit to record blood flow through the cannulated coronary artery. The test compounds were administered directly into the rubber tubing connected close to the coronary artery cannula. Coronary vasodil dti ng potency of the test compounds ~ 3 ~

was by calculating the dose required to produce 1007, increase of Cor. BF
(ED1oo pap), when the maximum responses to papaverine at a dose o~ 300 ~9 ia was expressed as 1007, response. Table 1 (column 2) shows ED1oo pap and the duration of action of coronary vasodilating ef,ect of test compounds.

(3) Beta-adrenoceptor blo~ing effects Beta-adrenoceptor bloc~ing effect of test compounds was determined according to the method of Tachikawa and Takenaka (Pharmacological studies on 1-(7-indenyloxy)-3-isopropylaminopropan-2-ol hydrochloride (YB-2); Arch. Int.
pharmacodyn., 202, 79-92, 1973) using male Wistar rats. The rats were pretreated with reserpine (8 mg/kg ip), 18 hr before experiments. The rats were anesthetized with pentobarbital sodium (55 mg/kg ip) and vagotomized bilaterally at the neck. The heart rate was measured with a cardiotachometer triggered by the QRS of the ECG (lead II) and recorded on a polygraph. After the control response to isoproterenol at a dose of 0.1 ~g/kg iv was obtained, the test compound was injected iv in increasing doses at 20 min intervals.
The mean dose producing 5C% blockade of the positive chronotropic response to isoproterenol (ED50) was estimated from dose-response curves obtained by plotting inhibition percentage against-1Og cumulative dose of the test compound (Table 1, column 3).
-- - -In this series of experiments, intrinsic sympathomimetic activity (ISA) was also evaluated~ The results were shown in Table 1 (colum 4), wherein "-"
represents that an increase in HR was scarcely observed; "+" represents that an increase in HR by 10 to 19 beats/min was observed; "++" represents that an lncrease in HR by 20 to 29 beatslmin was observed; "+++" represents that an Table 1. Summary of pharmacological effects of test compounds , .
(1) (2) (3) (4) .... _ Beta Exp. No. ~ B P Cor. BF ED1oo pap Duration Blocking ISA
i9v 9 (~) (~) ~g ia min ED50 .
1 0.1 -7 Z1 75 15 0.13 +++
0.3 -17 69 8 1.0 -Z9 10 645 60 0.31 0.3 -12 26 400 60< 0.73 12 0.3 -18 14 475 60< 2~58 1.0 -33 96 2~ 60< 0.70 16 1.0 -31 97 162 60< 0.39 17 1.0 -35 94 158 60< 3.53 18 0.3 13 20 285 60 3.11 23 1.0 -3~ 64 - 780 60< 0.03 24 1.0 -33 6Z 245 60 1.50 26 1.0 -3~ 43 - ~600 40 0.53 Z8 1.0 28 70 555 30 0.27 34 0.3 -18 3 175 60< 0.90 42 1.0 -13 8 515 60< 0.50 Diltiazem 0.3 -30 90 51 20 NT
Propranolol NT NT 0.063 NT = Not tested Medicaments containlng a compound or compounds ac^ording to the invention may be pre?ared by conventional methods using conventional car-iers or excipients.
Medicaments may con~ai~ one kind of ~Q compound or many kinds of the compound of t~ invention. The compound may e in free form or a salt. They may for example be t~oche, administered orally as tablet,/ pills, capsules, granules;
parenterally by in ~ venous or in~ramuscuIar injectioni uppositories; or other suitable forms for a~ministration adhesive tape, plaster, etc.
in liquid, fluid,- or solid state, for example ointmen~.
Conventional carriers or excipients used for the medicaments are non-to~ic solid or liquid pharmaceutical materials, and examples ~ere~f are la~tose, magnesium s~earate, s~arch, talc, gelatine, agar, pectine, arabia gum, olive oil, sesame oil, cacao butter, e~hylene glycol.
The appropriate dose is dete~mined in each case C~ider~g factors-such-as the symptom, age and sex of the pa~ient. For an adult a daily total of 1-200 mg is usually administered by intravenous i~jection in one to several doses.
The invention is further illustrated by the ollow-ing Reference Examples and Examples. In the follwing Reference Examples and Examples, mp. Anal, Cal, Fnd, and NMR are abbreviations for melting point, elementary analysis values, calculated, found, and nuclear magnetic resonance spectrum.

Reference Example 1 2 N ~f9b 02 N ~ 3 2 3 ~3~ CH2 00C ~ CC)OCH23 9~o CH2CH2Br CH3~?c CHCOOCH H C ~NI~cH

(1) o K~ NJ~D ~ OCH2 CH2 N~l H2 N NH2 ~ H2 O ~ CH3 oOC ~¢l~ Cooc~l3 o H C ' N CH3 (2) 2 N~ OC}12 CE~2 NH2 CH3 OOC ~ COOCH3 H C J~N CE~3 (1) In isopropanol were dissolved 23 g of 2-(2-bromo-ethoxy)-5-nitrobenzaldehyde, 11.5 g of 3-aminocrotonic acid methyl ester and 11.6 g of methyl acetoacetate, and the mixture was refluxed under heating for 7 hours. The reaction solutlon was cooled, and precipitated crystals were collected by hltration. The crystals were washed with methanol, and air-dried to give 33 g of crude crystals of dimethyl 4-[(2-bromoethoxy)-5-nitrophenyl]-2,6-dimethyl- 1 ,4-dihydropyridlne-3,5-dicarboxylate. The product was directly used for the next process without purification.
(2) In 25 ml of N,N-dimethylformamide were suspended 17 g of dimethyl 4-[(2-bromoethoxy)-5-nilrophenyl~-2,6-:~ 3 ~

dimethyl-1,4-dihydropyridine-3,5-dlcarboxylate and 7.4 g potassium ph~halimide, and the suspension was heated at 12~-130~C for 3 hours. The reaction mixture was pourted into 750 ml of ice~water, and precipitated c ystals were collected by filtration. The c-ystals was washed with water and air-dried to give 19.6 g of crude c~ystals of dimethyl 4-((2-phthalimidoethoxy)-5-nitrophenyl~-2,6-dimethyl-1,4-dihyropyridine-3,5-dicarboxylate.
(3) A solution of 12 g of dimethyl 4-~(2-phthalimido-e.hoxy)-5-~itrophenyl)-2,6-dimethyl-1,4-dihy~ropyridine-3,5-dicarboxylate and 6 ml of hydrazine hyorate in 240 ml of ethanol was refluxed under heating for 30 minutes. Precipitated crystals were filteled of~ ~le hot, and the filtrate was concentrated under reduced pressure to remove the solvent. After adding water ~o the residue, the produc~ was ~xtracted with ethyl acetate. The extract was washed with water, and dried over anhydrous sodium sulfate, and the solvent was distilled off ~nder reduced pressure. Crude crystals thus obtained were recrystallized from me~anol to give 6 g of dimethyl 4~
t2-(2-aminoethoxy)-5-nitrophenyl~-2,6-dimethyl-1,4-di-hydropyridine-3,5-dicarboxylate.
mp. 2 2 8 ~ 2 30 Anal (Cl9~7 ~0,) C (C~o) ~ (7~) N (Co) Cal S 6.~ 9 5.7 2 1 0.3 6 - 23 ~
NMR ~DM50--d6 ) ( ~) D r:: ) ; 2 ~ ~ ( 6 ~1, s .9~ (2~, ~) 3.g8 (6~, s) 4.~ 6 ( 2~, t ) S ~4 (1r, 5 ) Reference Example 2 (1) Cl~ S~ ~ B r ( CHz 1 E~ r ~ CH, S ~
OH O (C~I2)~ Br CHO CHO

.
A sol-ut~-on-of-18.3 ~ of 5-me~hylthiosalicylaledehyde, 235 g of 1,4-dibromobutane and 1.1 g of tet-a-n-bulyl-~m~ium h~x~n sulfate in 18 ml of water was he~ted O an aG~u~ so~ium hvdr~xice o~risingat 70-80 C. While s~irring,~l3.1 g of sodium hydroxide and 109 ml of water were added/dropwise over a period of 4 hours. Then, the formed mixture was heated for 2 hours. The mixture was cooled, and extracted with chloroform. The æ~tract (organic layer separated) was washed with water, dried over anhydrous magnesium sulfate, and concentra~ed under reduced pressure to give 32.2 g of a crude product of 2-(4-bromobutoxy)-5-methylthio-. , . ~ . : . ....
~ .~

~3~2~

(2) ~0 (C.'I7)~ Br ~0 (CHz )~ Br CHO

In 55 ml of dichloromethane w~s dissolved 10 9 g of2-~4-bromobutoxy)-5-me~hylthiobenzaldehyde, and ~he solution was cooled to O~C. A solution of 15.2 g of m-chloroperbenzoic acid in 165 ml of dichloromethane was added dropwise to the before-me~tioned dichloromethane solution over a pe iod of three hours. After 4 ho~rs, saturated aqueous sodium hydrogen carbonate was added to the reaction mixture to ~eutrallze it, and the m~L~ure was e.~tracted with chloroform. The ex~ract (organic layer separated) was washed wi~h saturated aqueous sodium hydrogen carbonate and water, dried over anhydrous ~gnesium sulfate, and concentrated under reduced pressure ~o give ' a-crude-product. The-crude product was recrystallized from chloroform-ether to give 7.8 g of 2-(4-bromobutoxy)--5-methylsulonylbenzaldehyde m~. 103-105 C

.. ,, .. , . ... ~ .

1 3 ~

(3) CH~ 07 S~ C H~ COCH2 COOCH3 O (CH7)~Br CH3 CHO H N~C =cHcoocH3 C~ O2 S ~
~O (CH2)~ Br H

?.6 g of 2-(4-bromobutoxy)-5-methylsuIfonylbenzaldeh7de, 2..6 g of methyl acetoacetate and 2_9 g of 3-~inocrotonic acid methyl este were dissolved in 16 ml of isopropanol, and the solu~ion was heated for 5 hours. After coolin~
precipitated crys~als were collected by filtra ~ and recrystallized from methanol to give 6.3 g of/4{2-(4-bromobutoxy)-.5-methylsulfonylphenyl~-2,6-dimethyl-1,4-dihydropyTidi~e-3,5-dicarboxylate.

mp. 191-201C

(4) ~ O ( CH2 )~ B r K N~
CH, OOC~COOCH3 H3 ~N CH3 C;~3 2 S~ O
~O (C~z)~
CH3 OOC~COOC~I, o H,C N CH, In 8 ml o N,N-di ethyl~orma~de were suspended 6~3 g of dimerhyl 4-t2-(4-bromobutoxy)-5-me~hylsu~fonyl-phe~y~ -2,6-dimethyl-1,4-dinydropyrldine-3,5-di-carboxylate and 2~2 g of potassium phthalimide, and the suspension was heated for l hour a~ 120-13~ C. The reaction m?~ture was poured i~to ice-water, and precipitated solid materials were collected by filt~ation to give 7.0 g or a c_ude produc_ or 4-l2-(4-phthalimidobu~o~y)-5-methylsuIronylphenylJ-2,6- -dimethyl-1,4-di'~dropyridlne-3,5-dicarbo~ylate. This product was used for che ne~t process without purirication.
~5) C~,0~ S o CH,OOC~COOCH, ~ H2N NH2 HqO
H, C N CH, C~, Oz S~
~O ( CH2 )~NHz CH,OOC~COOCH, H~ C N CH, A solution of 6.9 g of dimethyl 4-~2-(4-phthalimido-butoxy)-5-mechylsulfonylphenyl]-2,6-dimethyl-1,4-dihydropyr-dine-3,5-dicarbox71a~e and 5.9 g or hydrazire ~onydrate in~95 /. echanoi (wace~: 5 /l) was erlu.~ed under ~3~2~

for 6 hDurs the reaction soluticn hea~ing~ Ar~e_ cool_ng/ the solution was concent_ated under reduced pressure. The residue was eYtrac~dwith chloroform, and the extract was washed with wate_, dried over anhydrous magnesium sulfa~e, and concentrated under reduced pressure. Crude c ystals thus obtained were recrystallized from chloroform-ether to give 2.6 g of dimethyl 4~ 4-~minobutoxy)-5-methyl-sulfonylphenylJ-2,6-d~methyl-1,4-dihydropyridine-3,5-dicarboxylate.
m~. 184-186 C

Reference Example 3 (1) ~C=CHCOOCH2CH3 CH3CH2~CH2 COOCH2CH3 H2N
O ( C H2 )~ C 1 OZ N~
~O (CH2),,CI
CH3 CH~ OOC~COOCHz CH3 In 106 ml af dry benzene were dissolved 13.0 g of 2-(4-chlorobutogy)-5-nitrobenzaldehyde, 7.28 g of ethyl propionylacetate, 0;20 ml of piperidine and 0.62 ml of for 9 hours acetic acid, and the solution was refluxed/under heating while removing water by using Dean-Stark trap. After cooling the reaction solution, 6.~2 g of ethyl 3-2mino-crotonate was added to the solution, and the mix~ure was re~luxed under heating for 11 hours. Afte~ cooling cru~e the m~Yture, precipitated/crystals we_e collected by - 28 _ v ~3~2~

13.13 g of diethyl 2-ethyl-4-t2-(4-chlorobutoxy~-5-nit-o-phenyl~-6-methyl-1,6-dihydropyridine-3,5-dicarboxylate.
m~. 147-149~C
(2) O

~ O(CH2)~CI K N
H,C~I2OOC ~ COOCH2CHJ
H,C N _ CHzCHl H O~N o ~ o(CH2)~
CH,CH2OOC ~ COOCH2C~, H,CJ~NJ~CH2CH, In 8 ml of N ,N-dimethylormamide were suspended 10.26 g o diethyl 2-ethyl4-~2-(4-chlorobutoxy)-5-~it~ophenyl3-6-methyl-1,4-dihydropyridine-3,5-di-arDoxylate and 3.84 ~ of potassium phthalimide, and the suspension was heated for 1 hour at 120-130 C. The reac.io~ mix~u~e was poured i~o ice-wa~er, and prec-pitated solid ma~erials we~e collected by fil~ration to give 12.5 g of a crude product of diethyl 2-ethyl-4-~2-(4-phthal~midobutoxy)-5-nitrophenyl~-6-methyl-1,4-dihydropyridine-3,5-dicarbo~ylate. This product was used for the next process without puri~cation.

~ 3~3i~

(3) oz~ O
~o(CH2)~ N~ ~2 N NH2 H20 CH3 CH~ OOC j~COOC~7CH3 o H

OzN~f~
~0 ( CHz )4NH2 C H, CH2 00 C~h~ C O O CH2 C H3 ~I, C N C~I2 CHJ

A solution of 12.4 g of die hyl 2-ethyl-4-L2-(4-phthalimidobuto~y)-5-nitrophenyl~-6-methyl-1~4-dihydro-pyridine-3,5-dicarboxylate and 10.4 g of hydrazine mono-hydrate in 270 ml of 95 Z ethanol (wa~r: 5 %) was refluxed under heati~g for lO hours. After cooling the reaction solution, the solution was concentrated under reduced pressure, and the residue was extracted with chloroform. The ~tract was washed with watP~, dried ovel anhydrous magnesium-sul ate, and concentrated under reduced pressure. Crude c-ystals thus obtained we_e recrystallized from chloroform-ether to glve 6.4 g of diethyl 4-~2-(4-ami.nobutoxy~-5-nitrophenyl~ -2-ethyl- ¦
6-methyl-1,4-d-ihydropyridine-3,5-dicarboxylate.
m~. 173.5-175.5~C

Exam~le 1 O ~ ~C~ C~-C~
Oc~. C~ ~, O
C~. OOC~COOCa, - E. C--~CE, 0 ~, ~ oC~ CE h~C~EC~ -O-E ~ Nrl CE OE

4 g of d~methyl 4-~2-(2-aminoethoxy~-5-nitrophenyl3-2 t 6-dimethyl-1,4-dihydropyridine-3,5-dicarioxylate (obtained in Reference PYample l)and 1.5 g of glycidyl - phe~yl ether we_e dissolved in 2Q0 ml of methanol, and _ __ the miYture was zllowed to sta~d for 2 days at room temDerature. The reaction m; xture was conce trated , and the residue was subjected to column chromatography on silicagel, . ~he product was eluted with chloroform-; methanol (98:2 v/~). Crude crys~als we2e recrystallized from ethanol to give 1.8 g of dimethyl 4-~2-~2-(2-hydroxy-3-phenoxypropylamino)ethox~ -5-nitrophenyl~- ;
2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate.
mp. 189-190~C
28H33N3g ) C(%) H(%) N(%) C21 60.53 5.~9 7.56 - 31 - ~ $~

NMR (DMSO-d6) ~(pp~); 2.22 (6X, s) 3.47 (6H, s) 5.21 (lH, s) Exam~les 2-13 By following ~he same procedure as in Example 1, the following compounds were obtained.

- 32 - ~3~2~

~xample 2 OC~. C~C~. C~C 5z -O
0.~ 0~

C'.~ sOOC~ ~ COOCH, dLmethyl 4-[4-[2-(2-hydroxy-3-phenoxyproovlamino)-ethoxy]-3~itrophenvl]-2,6-di.methvl-1,4-dihydropvridine-3,5-dicarboxylate mp. i47 ~ ~4 - - Anal ( C23x~3N3os~
C (%) H (~o) N (,o) Cal 60.5 3 5.~ 9 7.5 6 Fnd 60.4 7 6.0 2 7.51 NMR ( CDC 1 3 ) ô (ppm3 ; 2.3 5 (6 H , s ) 3.6 8 (6 ~, s ) d.~ 6 (2 H, t ) 5.0 1 (1 ~, s ) - 33 ~ ~ ~ 2~
Example 3 ,~ O CEI rE~ ~r C~I . CE~C~

CF~ Ooc~C~OC~, H,C'~ CE, dimethyl 4~[5-[2-(2-hydroxy-3-phenoxypropvlamino)-ethoxy]-2-nitrophenyl]-2,6-dimethyl-1,4-dihydro-pyridine-3,5-dicar~oxylate ~morphus powder Anal ( C28E~N3O~ ) C (070) H (%) N (%) Cal 60.5 3 ~.~ 9 7.5 6 Fnd 60.4 1 6.0 6 7.41 NMR~. ( CDCl 3 ) (ppm) ; 2.3 2 (6 E, s ) 3.5 8 ( 6 R, s ) 5.8 6 (1 ~, s ) -~ - 34-Example 4 C~33 ~ OCH2 CHZ NHCE[2 CIHCH2 -O-CH3 > CHCH2 2 C ~2 CH2 CEI<CH OEI

diisobutyl 4-[2-12-(2-hydroxy-3-phenoxypropylamino)-ethoxy]-5-nitrophenyl]-2,6-dimethyl- 1 .4-dihydropyridine-3.5-dicarbo~rlate mp. 165~166C
Anal (C34H4sN30s) C~%) H(%) N(%) Cal 63.83 7.09 6.57 Fnd 63.55 7.13 6.49 NMR (CDCI 3) (ppm); 0.84 (12H, dd) 1.86 (2H, m) 2.32 (6H, s) 3 . 78 (4H, d) 5.40 (lH, s) ~J

Example 5 ~` OCH2 CH2 NHCH2 CHCH2 -o-@~
CH3 (CH2 )5 -2 C ~ C2 (CH2 )5 3 OE~

dihexyl 4-12- [2- (2-hydroxy-3-phenoxypropylamino)ethoxy] -5 -nitrophenyl]-2,6-dimethyl- 1 ,4-dihydropyridine-3.5-dicarboxylate mp. 89 ~ 90C
Anal (C38Hs3N3Os) C(%) H(%~ N(%) C~l 65.59 7.68 6.04 Fnd 65.35 7.78 5.99 NMR (CDCl 3) S (ppm); 0.84 (6H, t) 2.30 (6H, s) 5.36 (lH, s) ~ 3 ~

Example 6 O N~
OCE~ C~L ~CH7CH CH~
OE~ -CH.O(CXL_ .C ~ ~Co (CHL`~OCH

bis(2-methoxyethyl) 4-[2-[2-(2-hydroxy-3-phenoxv-propylamino)ethoxy]-5-nitrophenyl]-2,6-dimethyl-1,4-dihydropyridin~-3,5-dicarboxvlate.

mp. 109 - 110 C

Anal ( C/2 E~Il~. OIl) ~ C(~) E(~) N(~) Cal 5 9.71 6.d 2 6.5 3 Fnd 5a"S7 6.36 6.44 ~M~ ( CDCl~
(ppm): 2.'~ 8 ( 6:E~, s ) 2.6 3.~ ( 4:EI7 m ) 3.28 ( 6H, s ) 3.~18 ( 4H, t ) 5.36 ( lH, s ) , ~3~2~

E~ample 7 O
~JLOCEZ cx~NHca c~ c~
, OEi CH O C ~ CO (C~ CH.
~ CR

methyl octvl 4-[2-[2-(2-hydroxy-3-phenoxyproPyl-amino)ethoxv]-5-nitrophenyl]-2,6-dimethyl-1,4-dihvdro-pyridine-3,5-dicar~oxylate Amorphous powder Anal ( C3s ~7 N3 09 ) C (O H (~) N (~) Cal 6 4.3 0 7.2 5 6.4 3 Fnd 6 4.~ 3 7.4 6 6.d 8 NMR ( CDC 1 ~ ) ô (ppm); 0.8 8 ( 3H, t ) 2.32 ( 6H, s ) 36d (3E, s) 5.~ 0 ( 1~, s ) - 38 - ~3 Example 8 ~ o(C ~ ~NECN~C~
OE~
C~.'2 C~ ~CO C~Iz ~3C N C~

dimethyl 4-[2-(3-(2-hydroxy-3-phenoxypropylamino)-propoxy]-5-nit_ophenyl]-2,6-dimethyl-1,4-dihydro-pyridine-3,~-dicarboxylate amorphous powder Anal( C29 H.5 N3 Og ) C(~) H(~) N(~) : Cal61.1 S 6.1 ~ 7.3 8 Fnd6 Q.l 6.4 8 7.1 0 .¦

.. . NMR (CDCl3 ) 8(ppm); ~0- '~2 0 ( 2H, m ) ~3 0 ( 6 ~, s ) 2.8~3.0 (4H, m ) 3.6 0 (5 ~, s ) d0~ O (d H, m ) 5.32 (lH, s ) ..

, ~. !
~ .

_ 39 _ ~3~2~

Example 9 0 .
~ O (C~)~ NnCH rH--ca~
OE~
c~, o c ~ ~ C~2 H~-C ~ CH.

d~methyl 4- [2- (4 (2-hydroxv-3-phenoxypropylamino)-butoxy]-5-nitro~henyl]~2,6-dime thyl-1, 4-dihydro-pyridine-3,5-dicarboxvlate amor?hous powder Anal( C~O H3~N3 09) C(~) H(~) N(~) Cal61 74 6.3 9 7.20 ~nd6 1 6 6 6.51 7.1 7 NMR ( CDCl3 ) ~(ppm); 1.6 O- æo (dH, m ) 8 ( 6H, s ) 7 0--~ O ( dX7 m ) 3.56 (6~, s ) 3. 2--d.l 6 ( dH~ m ) 5.3 ~ I s ) - ~o ~3~

Example 10 ~ lO(C~);N~CH ~ H~ -O~i CB CH~ 0~ C ~ 0 CFI
~ C ~ C~

I .
ethyl methyl 4-[2-~4-(2-hydroxv-3-phenoxypropylamino)-~utoxv]-5-nitrophenyl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate . ~ph ~ pcw~
Anal ( C3l E~ N. O~
C(~ ) N(~`
Cal 6 ~ 3 0 6.a 8 7.0 3 Fnd 6 ~3~ 6.7 7 6.9 5 ( CI)Cl3 ) ~(p~m); 1.1 6 .( 31I, t ) - _ 1.6 0~1 9 0 ( 4H, m ) 2.30 ( 6H7 s ) 2.60--2.90 (AH~ m) 3 a~l ( 3H, s ) 3.80~4.'70(6H, m) 5.~8 (lX, s ) ~3~2~

Exam?le 11 o b~lo(c~z~1O MiC~ C~-C~-~

C~zO C ~ CQ~C~
Ei. C

dimethyl 4-[2-[10-(2-hydroxy-3-~henoxv~ropylaminc)-decyloxy]-S-nitro?henyl]-2,6-dlmethyl-1,4-dihydro-pvridine-3,S-dicarboxylate amorphous powder Anal ( C.~ E~9 N3 09 ) C (~E ¢~) N (,~) Cal .64.~0 6.~9 Fnd 6 d ~ 77.6 5 6.~ 5 ., NMR (CDCl3 o (pDm); l.~ 0 ~ 1.6 0 (16 H, m ) 2.3 0 ( 6 ~, s ) 2.5 0 - 2.9 0 ( 4H, m ) ~.5 6 ( 6 ~7 5 ) 3.9 6--4.10 ( ~H, m ) 5.34( lH, s ) ~3~2~3~

Exam?le 12 ~
~O(CH~ zC~ d-~
OEi C~ O C ~zCH

Ei. C~
dime~hyl 4-[2-[5-(2-hydroxy-3-phenoxvpro~avlamino)-pentyloxy~-5-nitrophenyl]-2,6-dimethyl-1,4-dihydro-pyrdine-3,5-dicar3Oxylate amorphous powder Ana1 ( C.l E g N3 G~J ) C(~ ) N (~) Cal 6 ~30 6.5 8 7.0 3 Fnd 6 ~43 6.8 / 7.1 8 NMR ( CD~
~(p~Jm);l.d 0~ 1.9 0 ( 6 H, m ) 3 0 ( 6 H, s ) ~ 6 0~ ~90 ( 4 X, m ) 3.~ 6 ( 6 ~, s ) 3.~0 ~ 4~ 0 ( ~ X, m ) 5.3 0 ( l E, s ) "?

` ` ~ 3~

Example 13 z~
~O(CH_)r NE~ICH. t~
¦ OH
C~2o.C ~ r~o CH

dimethyl 4-[2-[6-(2-hydroxv 3-phenoxvpropvlamino)-hexvloxv]-5-~itrophenyl~-2,6-dimethyl-1,4-dihydro-pyridine-3,5-oicarboxvlate amorphous powder Anal ( C3~ F~ Og) C (~ ) N (~!
: Cal 62.8~ 6.7 6 6.8 7 Fnd 6558 6.8 3 6.88 NMR ( CDCl. ) ~(ppm);1.40~ 1.6 0 (8 ~, m ) 2.3 0 (6 ~, s ) 2.60~ 2.9 0 (4 ~
3.60 ( 6~7 s ) 3.90--4.1 0 (4H, rn ) 5.32 (lH, s ) ~ample 14 ~ Cll~j!, _,;~ C~,hECE~

In 30 ml of N,N-dimethylformamide were dissolved 2 g or dimethyl 4-~2-(2-aminoethoxy)-5-n~t~ophenylJ-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate and 0.6 g of stylene oxide, and the solution thus ~ormed was allowed to stand for 2 days at room temperature.
; The reaction solution was concentra~ed unde_ reduced pressure, and the residue was subjected ~o silica gel column chromatography. The product was eluted wi~h chloroform-metha~ol (95:5 v/v). Crude c-ystals was recrystallized from ethyl acetate to give 500 mg of dimethyl 4-~2- L2- (~-hydroxyphenethylamino)ethox,v~-5-nitrophenyl~2,6-d~methyl-1,4-dihydropyridine-3,5-di-carboxylate.
~ - m~. 135-137 C
Anal (C27x3lN308?
C(%) X(~) N(%) Cal 61.71 5.95 8.00 Fnd 61.88 5.84 7.94 ,NMR (DMSO-d6 ) S~p~m) 1.34 (3H, s) ~ ~5 ~ ~ 3 ~

3.58 (3H, s) 4,20 (2H, t3 4.82 (lH, t) 5.36 (lH, s) Example 1 5 ~\O (CH2 )~ NH2 CH3 2 N ~`0 (CH2 )4 NHCH2 CHCH2 --~
CH3 OOC ~OHOCH3 OH

In 1,300 ml of methanol were dissolved 13 g of dimethyl 4-[2-(4-aminobutoxy)-5-nitrophenyl]-2,6-dimethyl- 1 ,4-dihydropyridine-3,5-dicarboxylate and 4.5 g of glycidyl phenyl ether, and the solutlon thus formed was refluxed under heating for 16 hours. The solvent was distilled off under reduced pressure. The residue was subJected to silica gel column chromatography, and the product was eluted with chloroform-methanol (96:4 v/v). Crude crystals were recrystallized from ethanol to give 9 g of dlmethyl 4-[2-~4-(2-hydroxy-3-phenoxypropylamino)-butoxy]-5-nitrophenyl]-2,6-dimethyl- 1 ,4-dihydropyridine-3,5-dicarboxylate.
^' ~p. 13L-133'C

~nal (C30~37N3~) C(g~) ~(%) N(~) Cal 61.74 6.39 7.20 ~nd 61.61 6.d~ 7.21 NMR (CDCl~) ~:(p~m); L.6-2.0 (4~, m) 6.6-7.1 (3~, m) 2.28 (6a, s) 7.1-7~4 (3~, m) 2.7-2.g (4H, m) 7.9-3.2 (2~, m) 3.S~ (6~, s) 3.~-4.2 (5~, m) 5.30 (1~, s) . _ This produc- ~zs t~e~ted wi'i an ef~anolic solution of hv~rogen chloride to give hydroc~loric ac-d salt the~e~f, whic~ was re~_Is.~llized from e~anol to pro~ide dimethvl 4-[2-~4-(2-hydro~xv~ nenox~propYlamino)butoxy3-5 nitro-phe~vl~-2,6-cime~:~vl-1,4-dih~dropvridine-3, e -~ic-r~oxvlat~
hvarschlor~de.

m~. 117-120C
Anal (C30~37~309~ HCl- H20) C(~.) H(~.) N(%) Cl(%) (~al. 56 . 47 5 . 32 6 . 59 5 . 56 Fnd 56.68 6.3~ 6.32 5.53 E~ample 16 a) By following ehe same procedure as in E4~a~ple 15 using (S)-glycidyl phenyl ether, (S)-(-)-dimethyl 4-L2-~4-(2-hydrox~-3-2henox~Jpropylamino)blltox~ 5-nit~ophenyl~

2,6-dimethyl-1,4-di'nyd-opyridine-3~5-dicar~ox~Jlace was obtained.
~ mp. 144-L46 C
~ [~ 2d -~ ,1 (C-l . 08, MeoH ) ~ ~3 Anal (CloH37N3Og) C(%) H(%) N~%) Cal 61.74 6.39 7.20 Fnd 61.57 6.55 7.21 b) The product obtained at a) above was treated with an ethanol solution of hydrogen chloride to give hydrochloric acid salt thereof, which was recrystalli~ed from ethanol to provide a pure product of (s)-(-)-dimethyl 4-[2-2,6-dimethyl-l,ar-dihydropyridine-3,5-dicarboxylate hydrochloride.

mp. 187- 189C

[a]24 -12.5 (c=1.04, MeOH) Anal (C30H37N3Og.HCl) C(%) H(%) N(%) ~al 58.11 6.18 6.78 Fnd 58.00 6.31 6.71 Example 17 a) By following the same procedure as in Example 16 using (R~-glyciclyl phenyl ether, (R)-(+)-dimethyl 4-[2-[4-(2-hydroxy-3-phenoxypropylamino)butoxy]-5-nitropher~yl]-~,6-dlme-thyl- 1,4-dihydropyridine-3,5-dicarboxyla-te was obtained.

mp. 144- 146C

[c~]24 +2.2 (c=1.07, MeOH) Anal (C30H37N3Og) C(%) H(%) N(%) Cal 61.74 6.39 7.20 Fnd 61.58 6.56 7.17 ~ 3 ~
- 4~ -b) The produc~ ob~ained a~ a) above was t-eated an e_:~anoi soiu~-on o~ hvd-oc:~or-c ac-d LO g~ ve hvdroch'lor-c acid sal~ ~hereoL, wnich ~as ree-ya_all_ze~
a pure product OI
f-om ethanol to g-ve/(R)-( )-dime~hYl L-~2-~4-(2-hyd_oxv-3-?nenoy~7p.opylamino)butoY~,~-5-nit~opnenyl~-2,6-d~ e~hyl-1,4-dihyropyridine-3,5-dica_boxvlate hydroc:~lor-de.
~p. l91-lg3 C
t~3 24 T12.1 (c=1.0~ eOH) (C30~I372~309 .XCl ) C(~)E(7) N(%) Cal 58.11 6.18 6.75 Fnd 58.04 6.29 6.67 ~xam~le 18-o ~O( CHZ )~ ~fH2 ~ CHZ /C~ICH2- O~
CH3 CH'OOC~COOCHZ C~J O
X, C~HJ~CH, 2~r ~(CH2 ).~ NHCH2 CHCH2-O
CX,CX200C~D,COOCH2 CH~ OH
H~CJ~N~CH~
~ 5.2 ~ or In 500 ml o~ methanol we~e dissolved/diet~yl 4-(2-(4-aminobutoxy)-5 nit-ophenyl~-2,6-dimethyl-L,4-dihydropyridine-3,5-dicarboxylate and 1.7 g of glycidyl - and phenyl ethe~,/the solution thus formed was re~luxed under heating or 16 hours. The solvent was distilled or^ unde reduced pressure. The residue was subjected to silica ~el colu~n ch-om2~oc-a~hv~ and the ~roduct i ~3~2~
49 ~

c~ys.als was rec-ys~allized f_om erhanol to give 2.2 g of dlethyl 4-L2-t4-f2-hydroxy-3-phenoxypropylamino)-butoxv3-5-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3j5-dicarboxyla~e.
mp. 141-143~C
Anal (C32H41N39) C(%) H(%) N(%) Cal 62.83 6.76 6.87 Fnd 62.85 6.86 6.86 ~MR (CDC13) (ppm): 1.14 (6H, t) 1.5-2.0 (4H, m) 2.28 (6-~, s) 5.24 (lH, s) r~am~les 19-22 By ~ollowing the same procedure as in Example 18, ~he following com~ounds were obtained.

~ 3~2~

Examp le . 1 9 2~
~O(CH.!)~ NHCH2 C~ICX2-O~3 D-C~200C~COOCH2~ .
H~C N C~J
.. H

bis (cycloproovlmethyl) 4- [2- [4- (2-hyaroxy-3-phenoxyoropvl-amino ) buloxy] -5 -nit; OpherIvl] ~2, 6~irne~yl-i, 4~v~cDvridine-3 ,5-dicar~oxvlate mp. 148 --1 5 1 C
Anal ( C35 H4sN3 Oo~
C (%) H (%) N (~o) Cal 6 5.1 4 6.8 3 6.3 3 Frld 6 4.9 6 6.9 ~ 6.3 2 NMR ( C ij C i ., ) d (ppm); 0 ~ 0.6 ( 8 H, m ) 0.8--1.3 ( 2 H, ~r ) 1.4 ~ 2.0 ( 4 H, rn ) 2.3 0 ( 6 H, m ) 5.2 8 ( 1 H, s ) - 51 ~ 3 ~

Exam?le 20 2 1\1 ~, ~ O(CH.~),NHCH2CHCH~-O ~
CH,(C:i2)200C~COO(CH2)2CH, H,C N CH, d~yl 4-[2-[4~(2-hydroxy-3-phenoxypropylamino)butoxv]-5-nit~ophe~yl]-2,6-dimethyl-1,4-dinyc.ropyridine-3,5-dicaroboxylate mp. 1 4 8 ~ 1 5 1 C
Anal ( C3~ELsN3 09 ) C (~o) H (~70) N (/'o) Cal 6 3.83 7.0 9 6.S 7 Fnd 6 3.60 7.0 1 6.5 0 NM~ ( C D C 13 ) ; ~(ppm) ; 0.84 ( 6 H, t ) 1.2~ 2.0 ( 8 YL7 m ) 2.30 ( 6 H, s ) 5.28 ( 1 H, s ) ~ 3~2~
- ~2 -Exxmple 21 NO~
~ O(CH~ Hc-~2c~cH
CH2OOC ~ COOCH2 OH
H3C N CX, dimethyl 4-[2-[4-(2-hvdroxy-3-phenoxypropylamino)-butoxy] 4-nitrophenyl]-2,6-dimethyl-1,4-dihydro-pyridine-3,5-dicarboxylate m~. 122 ~ 124C
~nal ( C30H3~N3Og 0.5 H7O) C (C~o) H (%) N (%) Cal6 0.~0 6.4 6 7.0 9 ~nd6 0.7 1 6.4 2 7.04 NMR ( C D C 13 ) d(ppm) ;1.6 ~ 2.0 (4 H, m ) 2.3 0 ( 6 H, s ) 3.5 8 ( 6 H, s ) - 5.32( l H . s ) - 53 ~3~2Q~

Exam?le 2 ~ O(CH~ HCH7CHCH2-C. 3`C~ooC $~tcooC~'C 3 OH
H ~Cl diisoproovl 4-[2-[4-(2-hvdroxy-3-~henox~propyl-amino)butoxv-;-nitrophenyl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicar~oxylate hydrochloride mp.21 2 ~ 21 3 C
L~a1 ( C34 H4B N3 09 C 1 ) C (~) X (Go) N (7 ) Cal6 0.3 9 6.86 6.~1 Fnd6 0.1 9 6.92 6.24 NMR (pMSO-d~ ) ~(ppm) ; 0.9 0 ( 6 H, d ) 1.1 6 ( 6 H, d ) 2.2 4 ( 6 X, s ) 3.3 2 ( 6 H, s ) 4.74 ( 2 X, m ) 5.04 ( l ~, s ) E~aIn~1e 23 1312~8 CHJ 2S~
t- C H7 ~ CH CH Z ~ O
C-r1~ OOC~COOCH~ O
H3 C ~ C~ C~J O. S
~O(CHZ)~, NHCH~CHCH2-~

C~I~OOC~COOCH3 H
HJ C N CHJ

In 44 ml of methanol we~e dissolved 2.57 ~ of d~methyl 4-t2-(4-aminobutoxy)-5-~ethylsulfonyl~he~yl~-2,6-(ob~ned m Referenoe E~le 2) dime~hyl-1,4-dihydropyridine-3,5-dicarboxylate/and 0.83 g of glycidyl phenyl ethe~, and the solution formed was allowed to reac~ a~ room te~e~ature for 43 hours. The reac-icn solu~n c~no~t-ated under reduced pressure. The residue was subjected to silica gel column chromatography, and the product was eluted wnth chloroform-methanol (95:5 v/v). Crude c~ystals were recrystallized from ethanol-ethe~ to give 1.05 g of dimeth~l 4-~2-~4-(2-hydro~y-3-phenoxypropylamino)-butoxy~-5-me~hylsulfonylphenyl~-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate.
m~. 145-146~C
Anal (C3lH4oN2o9s~o 5 2 C(%) H(%) N(%) S(Z) Cal 59.50 6.60 4.48 5.12 Fnd 59.60 6.63 4.29 5.28 NMR (CDC13) ~(v~m) : 2.28 (6H, s) 2.98 (3H, s) 3.56 (6H, s) - 5~ 2~

E~{am~ l e s 2 ~ - 3 7 By following the sa;~e procedure as irl E~a~le 23, the following compounds we~e ob~ained.

~ 3~2~3 Exam?le 2 Cl ~b~O(CH.,)~NHCH~CHC~ O
CH300C ~ COOCX~ OH
H,C ~N CHJ

oime~hyl 4-[5-chloro-2-[4-(2-hycroxv-3-phenoxy-propylamino)butoxy]phenyl~2,6-dimet~yl-1,4-dihydropyridine-3,5-dicarboxylate amorphous powder Anal ( C30 H37 C 1 N2 7 ) C (%) E(%) N(%) Cal 6 2.8 8 6.5 1 ~.8 9 Fnd 6 2.71 6.~ 3 4.8 0 NMR ( C D Cl3 ) ~(ppm) ; 1.5 ~ 1.9 ( 4 X, m ) 2.2 8 ( 6 H, s ) 3.6 0 ( 6 H, s ).
5.24 ( 1 H, s ) - 57 ~ 2~

Example 25 CHJ 0~
~0( Cr;~ )z NHC.-I. CHCH~ ~ 0~9 CH~ OOC~C OOC~I~ OH
H,C N CH~

dimethvl 4-[2-[2-(2-hydroxv-3-phenoxypropylamlna)-e~hoxy]-;-methoxyphenyl] 2,6-dimethvl-1, G -dihydro-pvridine-3,5-~ic~ox~l 2te mp. 1 4 1 ~ 14 3 C
Anal ( C~sH36N2O~) C (~o) H(%) N(/o) Cal 6 4 a 3 6.7I ~.1 8 ~n~ 64.09 6.6 8 ~.08 N~R ( CD C 13 ) ~(ppm) ; 2.23 ( 6 X, s ) 3.56 ( 6 H, s ) 3.6 8 ( 3 H, s ) 5.2 8 ( 1 ~, s ) - 58 _ ~3~2~

Example 26 CX~ 0 ~ O(CH.,),NHCHzCHCHz-CH,OCC ~ COOCXI OH
H,C N CH, --d3me~hyl 4-[2-[4-(2-hydroxy-3-phenoxypropvlamino)-butoxy]-5-methoxypnenyl]~2,6-dimethyl-1,4-dihydro-pyridine-3,5-dicarboxylate amorphous powder Anal ( C3iE~oN~0~-0.5 H70 C (%) H~%) N(/o) _ ~a~ 6 ~.~ 6 7.1 5 4.85 Fnd 6 4.4 ~ 7.2 7 4.7 2 _ . ..

NMR (pyridine-d5) d(pp~) ; 2.5 1 ( 6 H, s ) 3.65 ( 9 H, s.like) 5.8 5 ( 1 H, s) .. . ..

_ 59 _ ~3~2~

Example 27 CH,l~n ~O(CH~ HCH2 CHCH2-~
CHJ OOC ~COOCH3 OH
HJC~ ~CH, dimethyl 4-[2-[4-(2-hyroxy-3-phenoxvpropylamino)butoxy]- .
5-methylphenyl]-2,6-dimethyl-1,4~dihydropyridine-3,5-dicarboxvlate amorphous powder - Anal ( C3~ XLo N~0~-0.5 H20) C (%) H (~o) N (C~c) C21 6 6.~ 9 7.3 6 4.9 9 Pnd 66.38 ,.36 4.9~

~ MR ( CD C 13 ) d (ppm) ; 2.21 ( 3 H, s ) _ 2.2 7 ( 6 H, s ) 3.a 7 ( 6 H, s ) 5.2 2 ( 1 H, s ) 6.1 7 ( 1 ~, s ) ~3~

~xample 25 C'-~ `o( cH2 ) 4NH

C~IJ OOC~C OOC~I~ O H
H3 C 1~ C H~ . HC1 . . . .

dimethyl 4-[2-[4-(2-hydroxy-3-phenox~propylamino)-butoxv]-5-methvlthiophenyl]-2,6-dimethyl-1,4-dihydro-pyridine-3,5-dicar~ox~ylate hydrochloride amorphous powder Anal (C31H~o~ 07 S HCl 0.8H20 c (,) -ri (70) ~ (,) c 1 ('! s (r70) Cal 58.58 6.76 4.11 5.58 5.04 Fnd 58.60 6.~1 4.25 5.79 5.24 NMR ( C D C 13 ) d (ppm) ; 2.3 0 ( 6 H, s ) 2.3 9 ( 3 H, s ) 3.5 4 ( 6 H, s ) 5.1 4 ( 1 H, s ) - 61 - ~3~d~.

Exa~l~ 29 Cl~, ~ O(CH~).NHCH.C'.I~H -CHJOOC ~ COOCH, OH
H,C HN CH, dimet~yl 4-[5-chloro-2-[2-(2-hvdroxv-3-Dhenoxypro~yl-amin.o)e~hoxy]phenv~-2,6-dimet~yl-1,4-dihvdro2yridin2-3,5-dicar~oxvlate mp. 1 8 4 ~ 1 8 6 C
Anal (C2sH33C1N7 07) C (~o) H(,'o) N(%) ~ - - Cal 61.70 6.1 0 5.1 4 Fnd 60.l 6.2 3 4.9 4 NMR ( C D C 13 ) a(ppm) ; 2.3 0 ( 6 H, s ) ~- ~.62 ( 6 X, s ~
5.26 ( 1 H, s ) Exam~le ~30 C~IJS
~ ( C H~ H C 'iZ C H C~

CH'OOCXJ?~COOCH' H
H, C N CH, _ H

dimethyl 4-[2-[4-(2-~vdroxv-3-phenoxypropylamino)-butoxy]-5-methylsul'inylphenyl]-2,6-dimethyl-l,a-dihydropyridi~e-3,5-dicarDoxvlate ; mp. 83 - 8 6 ~C
Anal ( C3I H~,o N2 8 ~; ' O. 5 H7 O) C (ao) H(~70) N(0,70) S (0~70) ~ Cal -61.07 6.78 4.59 5.26 Fnd 61.02 6.89 ~.41 5.28 NMR ( C D C 1 3 ) d (ppm) ; 2.~ 8 ( 6 H, s ) 2.6 5 ( 3 H, s ) 3.5 5 ( 6 H, s ) 5.~ 8 ( 1 H, s ) 63 ~ 3~ $~`

EXamD1e 3 1 Br~
~O(CHZ)4 NHCHZCHCHZ-O~,9 CH,OOC~COOCH~ H

dime~hyl 4 - [ 5-~romo-2-[4-(2-hydroxy-3-phenoxypropyl-amino)butoxv]phe~yl]-2,6-dime_hyl~l, 4 -dihydro-pyridine-3, S-dicar~oxylate m~. 8 3 ~ 8 5 C
Anal ( C30 H3lN~ 07 Br~
C (%) H(~o) N(70) Br(%) ~ Cal 58.35 6.04 4.54 1 ~94 Fn~ 58.50 6.28 4.36 1~44 NMR ( CD C13 ) a (pp m) ; 2.2 7 ( 6 H~ s ) 3.5 8 ( 6 H, s ) 5.2 1 ( 1 H, s ) 6.4 6 ( 1 H, s ) ~3~
- ~4 -Fxample 32 Cl ~fCI
~ O(CH~)~NHCH2ChCH7-C'~.,ooC ~ COOCH, OH
H, CH, dime~hyl 4-[3,5-dic~loro-2-[4-t2-hvoroxy-3-phenoxv-propvlzmino)butoxv]phe~yl]-2,6-cimethyl-1,4-dihydro-pvriaine-3,5-dicarboxylate m~. 7 2 - 74 C
- Anal ( C30 H 3~ N2 07 C12 H2 C (70) H(%) N(70) Cl(,o) Cal 57.60 6.1~ ~8 11.34 Fnd 57.90 6.35 4.33 lL42 NMR ( CDC 13 ) ~(ppm) ; 2.2 8 ( 6 H, s ) 3.62 ( 6 H, s ) 5.2 2 ( 1 H, s ) 6.0 7 ( 1 H, s ) - 65 - ~3 Examole 33 Br Br ~O(C~2)" ~THCH~CHCHz-O~/~
CH,OOC ~ COOC'.-1, OH
H,C ,N CH, H --dimethyl 4-[3,5-dibromo-2-[4-(2-hydroxv-3-phenoxvpro2yl-amino)butoxy]phe~yl]-2~6-dimethy~ 4-dihydropyridine ,5-dicar~oxylate amor~hous powder Anal ( C30H3~ 07 Br2 0 1 H2 ) C(,o) H(70) N(70) Br(70) C21 51.61 a.23 4.01 2~89 Fnd 51.38 5.36 3.gl 23.21 NM~ ( CDC13) ~(ppm) ; 2.2 8 ( 6 H, s ) 3.6 4 ( 6 H, s ) .2 6 ( 1 H, s ) 6.1 2 ( 1 H, s ) . j . . ~ j, ~3~2~

Exa~.ple 3 4 ~O(CH2)( NHCHzr-ICHz-C~
C.i,OOC ~ COOCH, OH
HlC N~CH

~;me~yl 4-[o-[4-(2 hyaro~v-3-phenoxvpropylamino)-butoxv]phenvl]-2, 6 -di~ethvl-1,4-cihydropvridine-3,5-dicarboxylate mp. 12 9 ~ 1 3 0 C
Anal ( C30H38NqOI) C (~o) H(7c) N(~o) Cal 6 6 a 0 7.1 1 5. 0 . . ~na 6 6.~ 0 7.3 4 5.0 4 NMR ( CDC 13 ) ~(ppm) ; 1.5 ~ 1.9 ( 4 H, m ) 2.2 8 ( 6 H, s ) 3.5 6 ( 6 H, s ) : 5.2 0 ( l H, s ) - 67 - 13~2~

Example O(CH.~)2~HC H2 CHCH~-O
~ OH

- H3C ~ CH3 HCl . . ... . , ... _ . .
dimethyl 4~[m-[2-(2-hydroxy-3-phe~oxvpropylamino)e~hoxv~-phenyl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate hvdrochlo~ide ~P- 1 3 6 ~ 1 3 9 ~
Anal ( C2sE3~Nz 07 HCl) C (jo) H(/o) N(%) Cal 6 1.48 6.4 a 5.1 2 Fnd 6 1~7 7 6.4 4 5.09 MMR ( CDCl3) ~(ppm); 2.28 ( 6 H, s ) 3.6 0 ( 6 H, s ) 5.2 4 ( 1 H, s ) .. ' ' ' jt - 68 - ~3~2~

Exam~le 36 ~, O(CH.2)~ NHC'rI2CHCH2~~

C ~I, O OC~[ C O O C A~J
H

dime~hyl 4-[mr[4-(2-hvdroxy-3-phenox~proDylamino)-butoxy]phenyl]~2,6-d~methyl-1,4-~ihydro~vridine-3,5-dicarboxylate , m~. 1 06 ~ 1075 C
Anal ( C3~E38~z 07 0.5 X2O) C ~%) ~(%) N (/~a) Cal 6 5 80 7.18 5.1 2 - Fnd 6 5.7 2 7.3 2 A 9 ( NMR ( CD C 1 3 ) ~ (ppm) ; 2.31 ( 6 H, ~) - 3.6 S ( 6 H, S ) 5.0 0 ( 1 H, 5 ) 6.0 4 ( 1 H, s ~ . . .

- ` 113i2~
6g --Exam~le 37 O(cH~ HcH2cHcH
~ OH

CHJOOC ~ COOCH, H~C N CH, dimethyl 4-[P-[4-~2-hydrox~-3-phenoxypropylamino)- -butoxy]phenyl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate mp. 8 3 ~ 8 5 C
Anal ( C30X38N2 o-J
C (/o) H(/o) N(~o) Cal 6 6.40 7.1 1 ~.2 0 ~ F~d 6 6.64 7.2 0 ~.08 NM~ ( CDC13) (ppm) ; 2.31 ( 6 H, s ) 3.6 4 ( 6 X, s ) 4.9 5 ( 1 ~, s ) 5.7 8 ( 1 H, s ) ~cam~le 38 O.l~
~O(CIi~), NHZ
+ Cr~ CHCH2 ~CH~
H, C~ CO ZCHJ O

.
YlO(CH2)~ NHCHZCHC~2~~OCH~
-- CH~O2C~CO2 CHJ H
HJ CJ~N~CH~

In 200 ml or methanol were dissolved 2 ~ of dimethyl 4-~2-(4-ami~obutoxy)-5-nit-ophenyl~-~,6-dlmethyl-1,4-dlhydropyridi~e-3,5-dicar~oxylate and 0.84 g or glycidyl 4~methoxyphenyl ether, and the solution was refluxed under he~ting for 3 hours. The solvent was distilled of under reduced pressure. The~residue was subjected to silica gel column chroma~ography, and the product was eluted with chlorofor~-me-hcnol (95:5 v/v). C.-~ae crys~als were rec,ystallized from a mixture of merhanol and ethyl ethe- to give 0.85 g of dimethyl a_[2 C4-~2-hydroxy-3-(p-methoxyphenoxy)-propylamino~butoxy3-5-nitrophenyl~2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate.
. 154-155'C

- 71~ 8~
Anal (C3lx3gN3Olo ) C(h) H(") N(/o) Cal 60 . 68 6 . 41 6 . 85 Fnd 60 . 57 6 . 49 6 . 75 N2~R ( Cr)C1 3 ) ( p~m) : 2.28 (6H, s) 3 . 56 (6H, s) 3 J6 (3H, s) 5. 30 (lH, s) E~cam~ le s 3 9 - 4 5 By following the s me procedure as in E~Yam~le 38, the following com~ounds we~e obtained.

- 72 - ~3 Fxample 3 9 2~b ~o(c~2)~ NHCH2CHCH2-(~9 CH300C ~ COOCH, OH Cl H,C HN CH, HCl dimethyl 4-[2-[4-[3-(o-chlorophenoxy)-2-hydroxy-propylamino]butoxy]-;-nlt-opnenyl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicar~oxylate hydrochloride amorphous powder Anal (C30 H38C 1~.3 07 HCl) C (70) H (/b) N (Co) Cal 5 7.8 8 5.9 9 6.7a Pnd 5 8.1 3 5.8 7 6.6 9 - N~ ( DMSO-d~) d (ppm) ; lM 1.8 ( 4 H, m ) 2.3 2 ( 6 ~, s ) 3.6~ ( 6 ~, s ) - . 5.2 6 ( 1 H, s ) , .

~ 3 ~

Example 40 02N~
Y`O(CH2)~ NHcH2cHcHz-~3 CH~ OOC~COOCH3 OH C~
H C N _CH, dime~yl 4-[2-[a-[3-(o-cyanophe~oxy)-2-hydroxv~ropyl-amino]-~utoxy~-5~nit~ophe~yl]-2,6-dimethyl-l,4-dihydro-pyridine-3,5 dicarboxYlate mp. 1 69 - 1 71 C
( C3~ H3~N~Og) C (%) H(~o) N (/o) C=l 5 l.1 8 ~.g 6 9.~ l P~d 6 l.06 5.9l 9.08 NMR ( CDC13) ~ (ppm) , 2.32 ( 6 H, s ) _ . 2.7 6 ( 2 H, t ) - 3.56 ( 6 X, s ) 5.2 4 ( l H, s ) ExamDle d 1 o".~r~, ~O(CH2)~ NHcHIzcHcH2 H~ C ~ ooCH, O H 6_~

dimethyl 4-[2-[4-[2-hydroxv-3~ naphthvloxv)propyl-amino]butoxv~-5-nitroDhenvl]-2,6-dime~hvl-l,a-dihvdropyridine-3,5-dicarboxvlate mp. 1 80 ~ 1 81 ~C
Anal ( C3~H3sN30s) C (~'o) X(Go) N(07o) Cal 6 4.4 ~ 6.~0 6,6 3 Fna 6 4.1 7 6.3 5 6.46 NMR ( CDC 13 ) ~(ppm) ; 2.2 6 ( 6 H, s ) 3.3 a ( 6 H, s ) 5.3 0 ( 1 H, 3 ) _ 75 _ ~3 Exam~le 4~

~O~ CH2 )~ NHCH2 CHCH2 -o{3NHCoCH, CH,OOC3~COOCE~, OH
H, C NH C H~

dimet~vl 4-[2-[4-~3-(p-acetamidophenoxy)-2-hydroxy~
p~opylamino]butoxy]-5-nitrophenyl]-2,6-die~hyl-1,4-dihvdropyridine-3,5-dic2r~oxYlate m~. 1 7~ ~ 1 76 C
Anal ( C'2 ~I~,oN4 lo) C (%) ~ o) ~J (/o) Cal 5 9.9 9 6.2 9 8.74 ~nd 5 9.9 8 6.3 9 8.64 NMR (CDCl~ ,DMSO-d~) .
~(ppm) ; 2.08 ( 3 H, s ) 2.28 ( 6 ~, s ) 3.54 ( 6 H, s ) 5.~8 ( 1 H, s ) - 76 - ~3~2~

Exam~le ' '~b ~OCH3 C---CCH .'lHC'.i C~lCH -O~
CH, OOC~COOCH, OH
H

dimethyl 4-[2- [A_ (2-hydroxv-3-phe~oxypro~ylamino)-2-butinyloxy]-5-nitrophe~yl]-2,6-dimethyl-1,4-dihydro~yridine-3,5-dicar~oxvlate amorphous powder Anal ( C30H33N3Og 2 H7O) C (7O ) X (C'o) N (~'o) Cal 5 8.5 3 6.0 6 6.8 3 Pnd 5 8.1 3 6.3 5 7.0 9 NMR (CDC13) d (ppm) ; 2.3 0 ( 6 H, s ) 3.6 0 ( 6 ~, s ) 4.0 0 ( 2 H, s ) - 5.3 0 ( 1 H, s ) 77 ~ 2 ~ ~ ~
-Example 4 ~

1 ~ an s ~OC.i,CH=CXCH, ~HC H, CHCHI-O~
OH
1~
~,C ~--C-;3, HCI

dime~yl 4- [2- [ (E ) -4- (2-hyaroxv-3-phe~ox~roT?ylamino) -2-3:)utenyy] -Y5-nitrophenyl] -2, 6-dimethyl-l, 4-dihydro-pyricine-3, 5-dicarDoxvlale hydrocholorice mp . 1 7 1 ~ 1 7 3 C
Anal ( C30 H3~ 1~T3 09 C ~
C (%) H(%) ~(c/~o) 58.30 5.87 6.80 57.97 5.'~5 6.78 N~R . ( Dl`rIS O - d9 ) d ( ppm); 2.~ 4 ( 6 ~, s ) 3.4 6 ( 6 H, s ) 5.24 ( 1 ~I, s ) ''`` . - 78 Example 4~

o ~ ~ cis ~C~C~=C~c ~ c~ 8~c~,_0~
C~'C,~XCC~' H,C ~ C~, , HCI
dimethyl 4-[2-~(Z)-4-(2-hydroxy-3-phenoxypropylamino)-2 2utenyloxy]-5-~it~ophenyl]-2,6-dime~vl-1,,4-,dihydro-pyridine-3,5-dicar~oxylate hydrochloride mp. 1 91 ~ 1 9 3 C
Anal ( C30H3~ ~3 0~ Cl~
C () H(a,7a) N(~o) C21 S 8.3 0 5.8 7 6.80 F~d 5 8.0 S 5.8 7 6.8 8 NMR ( CDC 13 ) ~ppm) ; 2.2 8 ( 6 H, s ) 3.5 8 ( 6 H, s ) 4.7 0 ( 2 H, d ) ,5.3 4 ( 1 ~, 5 ) _ 79 _ ~L3 E~am~le 46 O'! ~
~O(CI~ )~ NH.
+ CH2- CHCH20 CH,CH200C~COOCH2CH, --H,C'~NJI`CH~ CH, O ~ N~
~ O(C Hz), N HCH ~ CH CH2 -O ~9 CHJC~2 OOC~COOCH2 CH, HIC N CHzC~I~

In 46 ml of methanol we~e dissolved 4~62 g of diethyl 4-L2-(4-aminobutoxy)-5-nit-opnenyl~-2-ehtyl-6-methyl-1,4-dihydropyridine-3,~-dicarboxylate and 1.46 g of glycidyl phenyl ethe~, and t~e solution formed was refluxed under heating for 15 hours. After cooling the re~ction ~o~ on,the solution was concent-ated unde- reduced pressure. The residue s;l~
~as subjec~ed to/coluD~ chromatog-aphy, and the product was eluted with chloroform-methanol(95:5 v/v), Crude c-ystals were recrystalllzed from e~hanol to give 1.22 g of diethyl 2-ethyl-4-~2-L4-(2-hydroxy-3-phenoxypropylamino)bu~oxy~-5-nitrophenylJ -6-methyl-1~4-dihydropyridine-3,5-dicarboxyla~e.
. 159.0-159.5C
Anal (C33H43N3O9) C(Z) H(~o). N(Z) Cal 63.35 6.93 6.72 ~nd 63 1~ 6 78 6.62 ~ 3 ~ 8 ~

N~IR (CDC13 ) (p;:m): 2. 30 (3H, s) 5.30 (lX, s) 6.57 (lH, s) Example 47 Medical composition:

~ormulation for 1,000 tablets:
Active compound 100 g Starch 185 g Lac~ose 25 g ~agnesium stearate 1.5 g - The ~bove com~onents were g~anulated using a s~arch paste as a binde- and then molted by a conventional manner.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A compound of the following formula or a salt thereof wherein R1 to R4 are C1 to C10 alkyl; R5 represents a nitro group or a lower alkyl-sulfonyl group; R6 represents hydrogen; A represents a single bond or a vinylene group, X
represents a halogen atom or a methanesulfonic or ethanesulfonic acid radical or a toluenesulfonic acid or benzenesulfonic acid radical; and m and n, which are the same or different, represents 0 or an integer of 1 to 5.

2. A compound according to claim 1 wherein R1 to R4 are lower alkyl 3. A compound according to claim 1 wherein -(CH2)m-A-(CH2)n- represents a C1 to C10 alkylene group.

6669/sza-d2